CN1946426A - Sustained release formulation for oral administration of HMG-CoA reductase inhibitor and method for the preparation thereof - Google Patents

Abstract

The sustained-release formulation of the present invention for oral administration of HMG-CoA reductase inhibitors can be prepared simply and economically, and by slowly releasing the HMG-CoA reductase inhibitor at a uniform rate, a constant drug level in the blood can be maintained for 24 hours. Similarly, the sustained-release formulation of the present invention can be effectively used to lower blood cholesterol and triglyceride levels.

Description

Sustained-release formulations for oral administration of HMG-CoA reductase inhibitors and methods for their preparation

technical field

The present invention relates to a sustained release preparation for oral administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which comprises a solid dispersion, a sustained release composite carrier and a gel hydration accelerator , wherein the solid dispersant includes an HMG-CoA reductase inhibitor, a solubilizer and a stabilizer; and a preparation method thereof.

technical background

Hyperlipidemia, or increased lipid levels in the blood, is a major cause of cardiovascular disease and arteriosclerosis. Representative examples of hyperlipidemia are hypercholesterolemia, familial dysbeta lipoproteinemia, diabetic dyslipidemia, nephropathy dyslipidemia, and familial mixed hyperlipidemia.

Several agents that lower blood lipid levels have been developed for the treatment of hyperlipidemia or hypercholesterolemia. Generally, these agents decrease the synthesis of lipoproteins or lipids in serum, or facilitate the clearance of lipoproteins or lipids from serum or plasma. Among these agents, inhibitors of HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, have been developed to reduce the concentration of lipoproteins or lipids in serum. Examples of HMG-CoA reductase inhibitors are mevastatin (U.S. Patent No.: 3,983,140), lovastatin, also known as mevinolin (U.S. Patent No.: 4,231,938), pravastatin (U.S. Patent No.: 4,346,227 and 4,410,629), lactones of pravastatin (U.S. Patent No. 4,448,979), velostatin and simvastatin, also known as synvinolin (U.S. Patent Nos. 4,448,784 and 4,450,171), rivastatin, fluvastatin, Torvastatin and simvastatin.

HMG-CoA reductase inhibitors have been widely used in the treatment of hyperlipidemia for decades to reduce total cholesterol and LDL-cholesterol concentrations in the body (Grundi, S.M, et al., N. Engl. J. Med. 319 (1): 24 -32, 25-26 and 31, 1998). Synthesis of mevalonate via the action of HMG-CoA is an early step in the cholesterol biosynthetic pathway, and HMG-CoA reductase inhibitors reduce total and LDL-cholesterol concentrations in serum by inhibiting mevalonate synthesis (Grundi, S.M. et al., N. Engl. J. Med. 319(1):24-32, 25-26 and 31, 1998).

However, most of such HMG-CoA reductase inhibitors are administered as immediate release formulations, which cause side effects such as hepatotoxicity, muscular dystrophy and rhabdomyolysis (Garnet, W.R. et al., Am. J. Cardiol. 78: 20-25, 1996; The lovastatin pravastatin study group, Am.J.Cardiol.71:810-815, 1993; Duzovne, CA. et al., Am.J.Med.91:25S-30S, 1991; and Mantel, GM . et al., Am. J. Cardiol. 66: 11B-15B, 1990).

Therefore, there has been a need to develop sustained-release formulations of HMG-CoA reductase inhibitors to prevent or alleviate side effects induced by fast-release HMG-CoA reductase inhibitors.

Numerous studies of sustained-release formulations of HMG-CoA reductase inhibitors have shown that most of the HMG-CoA reductase inhibitors absorbed in the body are metabolized in the liver (85% or more), while only those 5% or more Much less is transferred to the circulatory system throughout the body. Thus, the bioavailability of HMG-CoA reductase inhibitors to the systemic circulation is very low. Also, as an HMG-CoA reductase inhibitor primarily exerts its enzymatic activity in the liver, it is important to understand its pharmacokinetics in the liver as well as its bioavailability. Immediate-release formulations of HMG-CoA reductase inhibitors exhibit dose-dependent nonlinear pharmacokinetics, but cannot maintain their efficacy for long periods of time due to prolonged elimination half-lives due to saturation (volume limitation) phenomena that exist during hepatic metabolism . However, when a sustained-release formulation of an HMG-CoA reductase inhibitor is administered, although the blood concentration of the HMG-CoA reductase inhibitor can be lower due to hepatic metabolism than that of its rapid-release formulation, it is not possible due to its low blood concentration. Saturation occurs. According to recent studies, it has been reported that sustained release formulations of HMG-CoA reductase inhibitors show equal or slightly lower bioavailability than acid and lactone type rapid release formulations. However, its drug delivery efficiency to the target site was shown to be superior to that of rapid release formulations (John R, Amer. J. Cardio. 89:15, 2002). Therefore, sustained-release formulations can lower blood LDL-cholesterol levels more effectively than rapid-release formulations (Monlque P, Am. J. Drug Deliv. 1(4): 287-290, 2003).

Therefore, the present inventors have endeavored to solve the problems of the previously reported fast-release formulations of HMG-CoA reductase inhibitors and to develop new sustained-release formulations of HMG-CoA reductase inhibitors that remain in the blood through a slow and uniform release mechanism. A constant level of HMG-CoA reductase inhibitor dose, resulting in improved bioavailability with minimal side effects.

Contents of the invention

Accordingly, an object of the present invention is to provide a sustained-release formulation of an orally administered HMG-CoA reductase inhibitor for the treatment of hyperlipidemia, which can slowly release the HMG-CoA reductase inhibitor at a uniform rate for a long period of time.

Another object of the present invention is to provide a process for the preparation of said formulation.

According to one aspect of the present invention, there is provided a sustained release formulation for oral administration of an HMG-CoA reductase inhibitor, which comprises a solid dispersion containing an HMG-CoA reductase inhibitor, a solubilizer and a stabilizer; sustained release a composite carrier; and a gel hydration accelerator.

According to another aspect of the present invention, there is provided a method for the preparation of a sustained release formulation for oral administration of an HMG-CoA reductase inhibitor, comprising the steps of:

(1) mixing an HMG-CoA reductase inhibitor, a solubilizer and a stabilizer in a solvent to obtain a solid dispersion;

(2) uniformly mixing the sustained-release composite carrier and the gel hydration accelerator with the solid dispersant to form the first mixture;

(3) adding at least one pharmaceutically acceptable additive to the first mixture to form a second mixture; and

(4) Dry mixing and formulating the second mixture into a solid preparation.

Description of drawings

When in conjunction with the accompanying drawings, from the following description of the present invention, the above-mentioned and other objects and features of the present invention will be clearer, and the accompanying drawings show respectively:

Figure 1. is a graph showing the solubility comparison of the solid dispersions prepared in Examples 1-3.

Fig. 2. is a graph showing the elution rate of the sustained-release formulation prepared in Example 4, showing each rotational speed.

Figure 3. is a graph showing the comparison of the elution rates of the sustained release formulations prepared in Examples 4-6 depending on the amount of xanthan gum.

Figure 4. is a graphical representation describing the comparison of elution rates of sustained release formulations prepared in Examples 7-9 depending on the amount of HPMC 2208.

Fig. 5. is a graph showing changes in blood levels of simvastatin after oral administration of the sustained-release formulation prepared in Example 5.

Fig. 6. is a graph showing the pattern of distribution and excretion of simvastatin into bile after oral administration of the sustained-release formulation prepared in Example 5.

Detailed ways

The present invention provides a sustained-release formulation for oral administration of an HMG-CoA reductase inhibitor, which includes a solid dispersion containing an HMG-CoA reductase inhibitor, a solubilizer, and a stabilizer; a sustained-release composite carrier; and gel hydration acceleration agent.

The sustained release preparation of the present invention can be prepared by the following steps:

1) mixing an HMG-CoA reductase inhibitor, a solubilizer and a stabilizer in a solvent to obtain a solid dispersion;

2) uniformly mixing the sustained-release composite carrier and the gel hydration accelerator with the solid dispersant to form the first mixture;

3) adding at least one pharmaceutically acceptable additive to the first mixture to form a second mixture; and

4) Dry mix and formulate the second mixture into a solid formulation.

Since the sustained release formulation of the present invention for oral administration slowly releases the HMG-CoA reductase inhibitor into the blood at a uniform rate, it can maintain a constant drug level in the blood. Therefore, the sustained release formulation can be effectively used for the prevention and treatment of hyperlipidemia and arteriosclerosis by oral administration of a single dose once a day.

Hereinafter, the components of the sustained-release formulation of the present invention are explained in detail:

(i) Pharmaceutical active ingredients

HMG-CoA reductase inhibitors are drugs that treat hyperlipidemia and arteriosclerosis by reducing the level of lipoproteins or lipids in the blood. Representative examples thereof may include mevastatin (U.S. Patent No. 3,983,140), lovastatin (U.S. Patent No. 4,231,938), pravastatin (U.S. Patent Nos. 4,346,227 and 4,410,629), lactones of pravastatin (U.S. Patent No.: 4,448,979), velostatin, simvastatin (US Patent Nos.: 4,448,784 and 4,450,171), rivastatin, fluvastatin, torvastatin, simvastatin and pharmaceutically acceptable salts thereof. Among the above-mentioned HMG-CoA reductase inhibitors, simvastatin or a pharmaceutically acceptable salt thereof is preferable.

(ii) Solubilizer

Because the bioavailability of a poorly water-soluble drug decreases in proportion to its decrease in solubility, research on dissolving the drug and increasing its solubility is primarily used to develop sustained-release formulations of the poorly water-soluble drug. Since most HMG-CoA reductase inhibitors are poorly water-soluble compounds, solubilizers are used in the present invention to increase the solubility of the drug. Representative examples of solubilizers may include vitamin E TPGS (d-alpha-tocopherol macrogol 1000 succinate: Eastman), polyoxyethylene stearate (e.g., Myrj: ICI), polyethylene glycol, Polyoxypropylene-polyoxypropylene block copolymer (for example, Poloxamer: BASF) and the like. The sustained release formulation of the present invention includes the solubilizer in an amount of 0.05-20 parts by weight, preferably 0.1-10 parts by weight, based on 1 part by weight of the pharmaceutically active ingredient.

(iii) Stabilizer

The stabilizer used in the present invention may be any conventional stabilizer which prevents the oxidation of the drug. Examples of stabilizers are butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), erythorbic acid, ascorbic acid, and the like. The sustained-release formulation of the present invention includes the stabilizer in an amount of 0.01-0.5 parts by weight, preferably 0.02-0.1 parts by weight, based on 1 part by weight of the active pharmaceutical ingredient.

The present invention prepares solid dispersions with improved solubility by mixing drugs according to conventional methods such as spray-drying, solvent evaporation, finely pulverizing-wetting method, melting method and freeze-drying method Active ingredients, solubilizers and stabilizers.

In the case of preparation by spray-drying method, the solid dispersion of the present invention may further include a pharmaceutically acceptable solubilizing carrier. The pharmaceutically acceptable solubilizing carrier enables the uniform distribution of the solid dispersion in a smaller particle size to improve its solubility. Representative examples of solubilizing carriers can include starch and its derivatives (e.g., dextrin, carboxymethyl starch); cellulose and its derivatives (methylcellulose, hydroxypropylmethylcellulose); sugars ( lactose, sugar, glucose); silicic acids and silicates (natural aluminosilicate, magnesium silicate); carbonates (calcium carbonate, magnesium carbonate, sodium bicarbonate); polyoxyethylene derivatives; glycerol monostearate Esters etc.

(iv) Sustained release composite carrier

In the present invention, the sustained-release composite carrier used to form the hydrogel is preferably sodium alginate (Keltone® HVCR, Keltone® LVF, Kelcosol®, Kelset®: ISP, USA) and xanthan gum (Keltrol® F; Kelco® , USA), and the mixture may further include locust bean gum (Cesagum® LN1, LR 200; Cesalpinia, Italy). In general, the action of this ingredient is as follows: sodium alginate inhibits the appearance of the initial burst effect; xanthan gum contributes to structural fixation, which can make the difference in elution rate caused by physical forces such as gastrointestinal motility Minimized; and locust bean gum combined with xanthan gum can more strongly fix the structure. If the above-mentioned carrier components are used in a mixture in a certain mixing ratio, the initial burst release effect and the difference in elution rate caused by physical force can be reduced.

In the sustained-release formulation of the present invention, the sustained-release composite carrier may be used in an amount of 3-30 parts by weight, preferably 5-25 parts by weight, based on 1 part by weight of the active pharmaceutical ingredient. In the case of using a mixture of sodium alginate and xanthan gum as the sustained-release composite carrier, the amount of xanthan gum used is 0.1-10 parts by weight, preferably 3-6 parts by weight, based on 1 part by weight of sodium alginate. In addition, in the case of using a mixture of sodium alginate, xanthan gum and locust bean gum as a sustained release composite carrier, the amount of xanthan gum used is 0.2-10 parts by weight based on 1 part by weight of sodium alginate, preferably 3-6 parts by weight , the amount of locust bean gum used is 0.1-5 parts by weight, preferably 0.5-5 parts by weight.

(v) Gel Hydration Accelerator

The gel hydration accelerator used in the present invention plays an important role in forming a single uniform gelled core without forming a non-gelled core. When the sustained-release preparation of the present invention contacts the aqueous medium in the body, the gel hydration accelerator promotes its rapid hydration and allows water to penetrate into the inner core of the preparation in an equal and rapid manner. In the present invention, the preferred gel hydration accelerator is a mixture of propylene glycol alginate and hydroxypropylmethylcellulose (HPMC). In the above mixture, HPMC with a viscosity of 4,000-100,000 cps is preferred, and the amount of propylene glycol alginate used is 0.05-20 parts by weight, preferably 0.1-10 parts by weight, based on 1 part by weight of HPMC.

In the sustained release formulation of the present invention, the gel hydration accelerator is used in an amount of 0.1-20 parts by weight, preferably 0.5-15 parts by weight, based on 1 part by weight of the pharmaceutically active ingredient.

Furthermore, in order to prepare a solid preparation for oral administration, the sustained release preparation of the present invention may further include at least one pharmaceutically acceptable additive. Representative examples of pharmaceutically acceptable additives are binders, lubricants, sweeteners, excipients and the like. The binder used in the preparation of solid preparations can be any pharmaceutically acceptable binder, such as polyvinylpyrrolidone (PVP), gelatin, hydroxypropyl cellulose, kofovidone (Kollidon) VA64: BASF, Germany) and the like.

The lubricant used in the present invention can be any pharmaceutically acceptable lubricant that increases flow. Representative examples thereof may include light anhydrous silicic acid, zinc or magnesium stearate, and the like.

Furthermore, the present invention provides methods for the preparation of sustained release formulations for oral administration of HMG-CoA reductase inhibitors.

Method of the present invention comprises the following steps:

(1) mixing an HMG-CoA reductase inhibitor, a solubilizer and a stabilizer in a solvent to obtain a solid dispersion;

(2) uniformly mixing the sustained-release composite carrier and the gel hydration accelerator with the solid dispersant to form the first mixture;

(3) adding at least one pharmaceutically acceptable additive to the first mixture to form a second mixture; and

(4) Dry mixing and formulating the second mixture into a solid preparation.

In addition, the method of the present invention may further include the step of coating the surface of the solid preparation prepared in step (4) with any pharmaceutically acceptable coating agent. Representative examples of coating agents may include hydroxypropylmethylcellulose, polyethylene glycol, polyvinyl alcohol, and the like.

In step (1), the solid dispersion can be prepared by conventional methods, such as spray-drying, solvent evaporation, fine pulverization-wetting, melting and freeze-drying, and the preferred particle size diameter is 5-200 μm. The solvent used to dissolve the HMG-CoA reductase inhibitor, solubilizer and stabilizer is preferably water, ethanol or dichloromethane.

The dry mixture obtained in step (4) can be made into soft and hard capsules according to conventional procedures. In a preferred embodiment of the present invention, the second mixture of step (4) can be compressed into tablets according to the direct tablet forming method or formulated into tablets after compression and pulverization.

A typical daily dosage for oral administration of a sustained release formulation of an HMG-CoA reductase inhibitor may be in single or divided doses.

The following examples are intended to further illustrate the invention without limiting its scope.

Example 1-3: Preparation of solid dispersion

Simvastatin (Hanmi Fine Chemicals Co., Ltd., Korea), Vitamin E TPGS (Eastman, USA), BHT (UENO Fine Chemicals Co., Ltd., USA) and HPMC 2910 (Shin-Etsu, Japan) were dissolved in ethanol, and each resulting mixture was spray-dried to obtain a solid dispersion with an average particle size equal to and less than 100 μm. As a comparative group, a solid dispersion was prepared by mixing only simvastatin and HPMC 2910 in ethanol (comparative example 1).

<table 1> Composition (mg/dispersant) Simvastatin Vitamin ETPGS BHT HPMC 2910 Comparative example 1 40 x x 100 Example 1 40 80 2 100 Example 2 40 40 2 100 Example 3 40 40 2 50

Example 4-12: Preparation of Oral Sustained Release Formulations

According to the same method described in example 1, mix simvastatin, vitamin E TPGS, Myrj, BHT and HPMC 2910 to prepare solid dispersion. Then, each solid dispersion was mixed with sodium alginate (ISP, USA), xanthan gum (Kelco, USA), locust bean gum (Cesalpinia, Italy), propylene glycol alginate (ISP, USA), HPMC 2208 (Shin -Etsu, Japan) and kafovideon were mixed for about 30 minutes. Magnesium stearate and light anhydrous silicic acid powder (finer than a 40 mesh screen) were added to the mixture and mixed for 5 minutes. The resulting mixture was shaped into pieces using a shaping formulator, and the pieces were then crushed into granules with a particle size of 20-80 mesh. The granules are then formulated into tablets in a formulator according to conventional compression methods. Next, oral sustained-release formulations of Examples 5-12 were prepared in the same manner as above. The amounts of each component are shown in Tables 2-4. Meanwhile, HPMC2208 used in all Examples has a viscosity of 100,000 cps, and Examples 11 and 12 respectively use lovastatin and fluvastatin instead of simvastatin as pharmaceutical active ingredients.

<Table 2> Ingredients (mg/tablet) Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Simvastatin 40 40 40 40 40 40 40 Vitamin ETPGS 40 40 40 40 40 40 0 Myrj 0 0 0 0 0 0 40 BHT 2 2 2 2 2 2 2 HPMC2910 50 50 50 50 50 50 50 sodium alginate 36 36 36 36 36 36 36 xanthan gum 100 120 160 160 160 160 120 Locust Bean Gum 60 60 60 60 60 60 60 Propylene glycol alginate 36 36 36 36 36 36 36 HPMC2208 160 160 160 40 80 120 160 Kafavidon 35 35 35 35 35 35 35 light anhydrous silicic acid 10 10 10 10 10 10 10 Magnesium stearate 2 2 2 2 2 2 2

<Table 3> Ingredients (mg/tablet) Example 11 Lovastatin 60 Vitamin E TPGS 20 BHT 2 HPMC 2910 50 sodium alginate 36 xanthan gum 150 Locust Bean Gum 50 Propylene glycol alginate 30 HPMC 2208 110 Kafavidon 35 light anhydrous silicic acid 10 Magnesium stearate 2

<Table 4> Ingredients (mg/tablet) Example 12 Fluvastatin 80 Vitamin E TPGS 60 BHT 2 HPMC 2910 60 sodium alginate 40 xanthan gum 150 Locust Bean Gum 80 Propylene glycol alginate 35 HPMC 2208 110 Kafavidon 35 light anhydrous silicic acid 10 Magnesium stearate 2

Test example 1: Solubility test of solid dispersant

According to the first basket method (1st Basket method) described in the Korean Pharmacopoeia, according to the following conditions, using the dissolution rate detection system, the solid dispersion of Comparative Example 1 and Example 1-3 and the former powder of simvastatin as a control group in Solubility tests were performed in distilled water.

Dissolution testing system: Erweka DT 80 (Erweka, Germany)

Effluent: 900ml distilled water

Effluent temperature: 37±0.5℃

Rotation speed: 50, 100 and 150rpm

Analytical method: liquid chromatography

Column: Cosmosil C ₁₈ (Nacalai tesque)

Mobile phase: Acetonitrile/pH 4.0 buffer solution ^*

    Flow rate: 1.5ml/min

  Detector: UV spectrophotometer (238nm)

  Injection volume: 20μl

^* A pH 4.0 buffer solution was prepared by mixing 3 ml of glacial acetic acid and 1 L of distilled water and adjusting the pH of the mixture to 4.0 with NaOH.

As shown in Figure 1, it was found that the solid dispersions of examples 1-3 prepared by spray-drying the mixture of simvastatin, vitamin E TPGS and HPMC were more effective than the solid dispersions of comparative example 1 prepared by mixing simvastatin and HPMC and Both raw simvastatin powders showed higher solubility, and their solubility was more proportional to the amount of vitamin E TPGS than HPMC.

Test Example 2: Dissolution Test on Rotational Speed

According to the 1st Paddle method described in the Korean Pharmacopoeia, the preparation prepared in Example 5 was tested for in vitro dissolution under the following conditions. The amount of simvastatin eluted from the preparations during the assay was determined by liquid chromatography at 1, 2, 4, 6, 8, 10, 12, 16, 20 and 24 hours after dosing. Each sample was reacted with 40 mg of pre-washed MnO2 (as per USP simvastatin tablet 1) for 30 minutes and centrifuged at 3,000 rpm for 5 minutes. Then, the absorbance of each sample was measured using a UV spectrophotometer and the actual absorbance was calculated by subtracting the absorbance at 257 nm from the absorbance at 247 nm.

Dissolution testing system: Erweka DT 80

Effluent: 0.01 M sodium phosphate buffer (pH 7.0) containing 5% sodium lauryl sulfate (SLS)

Effluent temperature: 37±0.5℃

Rotation speed: 50, 100 and 150rpm

Analysis method: UV spectrophotometer (247nm and 257nm)

Calculation of Elution Quantity: Cumulative Release Quantity

As shown in Figure 2, it was found that the simvastatin formulations of the present invention did not show any significant difference in the dissolution rate by changing the rotation speed, which means that the bioavailability was reproducible.

Detection Example 3: Dissolution Detection of Xanthan Gum Amount

According to the same method described in Test Example 2, the preparations prepared in Examples 4-6 were tested for in vitro dissolution at 100 rpm.

The results in Figure 3 show that the dissolution rate of the drug is inversely proportional to the amount of xanthan gum, which indicates the function of xanthan gum as a sustained release vehicle. Therefore, it can be deduced that hydrogels with stronger strength are formed by increasing the amount of xanthan gum.

Detection example 4: Dissolution detection of HPMC 2208 amount

According to the same method described in Test Example 2, the preparations prepared in Examples 7-9 were tested for in vitro dissolution at 100 rpm.

As shown in Fig. 4, it was found that the dissolution rate of the drug was proportional to the amount of HPMC until the amount of HPMC reached a certain concentration, after which it became inversely proportional to the amount of HPMC. These results show that HPMC functions as a gel hydration accelerator, but when added at high concentrations, it is able to act as a sustained release vehicle.

Test Example 5: Tests for Oral Absorption and Distribution/Excretion into Bile

In order to compare the bioavailability and sustained-release effect of the orally administered formulation of the present invention and to examine its efficacy on the liver as the target site of the HMG-CoA reductase inhibitor, when administered orally to rats, the bioavailability and distribution/ Excreted into bile for the following assays. At this time, the sustained-release formulation prepared in Example 5 was used as a test sample, and ZOCOR(R) (MSD Co., Ltd., Korea), known as a rapid-release formulation of simvastatin, was used as a control sample.

Male Sprague Dawley rats (average body weight: 250 g) at 14-15 weeks were divided into two groups, 5 rats in each group. The mice were allowed free access to food and water for more than 4 days in order to adapt to the new environment. Then, the mice were fasted for 48 hours, but they were allowed to drink water ad libitum. Before the administration of each sample, the rat was anesthetized and its hands and feet were tied, and then the arteries and veins of the femoral artery region and the bile duct were surgically inserted, respectively, and blood and bile were collected simultaneously. Fluid losses are replaced by injections of saline through a tube inserted into a vein. Then, each test and control sample was filled into capsules for oral administration to rats in an amount equivalent to 10 mg/kg of simvastatin, and were orally administered to rats using appropriate injection tools, respectively. Blood samples were collected from tubes inserted into the arteries and veins of the rats before dosing, and at 0.5, 1, 1.5, 3, 5, 7, 9, 12 and 24 hours after dosing. Bile samples were collected from tubes inserted into the murine bile ducts at 1, 2, 3, 5, 7, 9, 12 and 24 hours after dosing.

The following analyzes were performed on the blood levels and the partition pattern of simvastatin in bile.

Add 200 μl of methanol as an internal standard to each 100 μl of bile and blood samples, and shake the mixture to obtain extracts. The extract was centrifuged at 3,000 rpm for 10 minutes to obtain a supernatant, which was filtered through a filter paper having a pore size of 0.22 μm. Then, the filtrate was subjected to LC-MS analysis under the following conditions. The results of the analysis are shown in FIGS. 5 and 6 .

Column: Waters Oasis HLB (2.1×50mm)

Mobile phase: acetonitrile concentration gradient system, water and 10 mM NH ₄ OAc (adjust pH to 4.5 with formic acid)

Injection volume: 50μl

Flow rate: 0.3ml/min

Detection: SIR mode m/z: 419.4 (simvastatin), 435.3 (simvastatin acid)

As shown in Figure 5, the sustained release formulation of the present invention showed a Cmax of 79.4ng/ml and an AUC of 249.0ng·hr/ml, which were slightly lower than the values of the rapid release formulation (Cmax of 88.1ng/ml and AUC of 266.2ng·hr/ml). hr/ml AUC), but it exerted the ideal level for sustained release effect. Furthermore, the results in Figure 6 show that most of the sustained release formulations of the present invention are present and metabolized in the liver, which indicates the fact that the sustained release formulations are more effective for the liver than the rapid release formulations. The sustained release formulation of the present invention is the most suitable formulation for oral administration of HMG-CoA reductase inhibitors considering that HMG-CoA reductase inhibitors are more than 95% metabolized in the liver to be considered effective.

Test Example 6: Effects on Lowering Cholesterol and Triglyceride Levels

In order to test the therapeutic effect of the sustained-release preparation of HMG-CoA reductase inhibitor on hyperlipidemia caused by a high-cholesterol diet, the sustained-release preparation of the present invention was administered to induced hyperlipidemia rats, and blood cholesterol was measured. and changes in triglyceride concentrations.

Specifically, a high-cholesterol diet for inducing hyperlipidemia was prepared and a pathological model was established according to the method described by Niiho et al. (Yakugaku Zasshi 110:604-611, 1991). A high-cholesterol diet was prepared by grinding common animal feed for normal diets through a 40-mesh sieve and mixing with 5% cholesterol, 0.25% cholic acid, and 2.5% olive oil.

Twenty-four 4-5 week old male Sprague Dawley rats were used in the following experiments. After the rats were weighed, they were evenly classified according to their average body weight and divided into 4 groups, each group consisting of 6 rats with an average body weight of 202±5 g. Let the rats adapt to the cage environment with a temperature of 23±2°C and a relative humidity of 55±5%.

The first group is a control group, which is fed with a high-cholesterol diet during the experiment and is not given therapeutic drug treatment; while the second group is fed with a high-cholesterol diet and administered ZOCOR(R) corresponding to 5 mg/kg simvastatin once a day . The third group was fed with a high-cholesterol diet and administered the sustained-release formulation prepared in Example 5 corresponding to 5 mg/kg simvastatin once a day; and the fourth group was a normal group that had not received a high-cholesterol diet and therapeutic drugs.

Two weeks after drug administration, rats were sacrificed and serum samples were collected from each group. The concentrations of total cholesterol and triglyceride in blood were measured according to a conventional enzymatic reaction method, and the results are shown in Tables 5 and 6.

<Table 5> animal group Total Cholesterol ^* (m/dl) Ratio of cholesterol level to control (%) Group 1 (control) 671.5±84.1 100 Group 2 (ZOCOR ^(R )) 567.9±93.2 84.6 Group 3 (sustained release formulation of Example 5) 453.0±77.0 67.5 Group 4 (Normal) 81.0±8.2 - ^* Mean concentration of total cholesterol ± standard deviation

<Table 6> animal group Triglycerides ^* (mg/dl) Ratio (%) of triglyceride level to control Group 1 (control) 242.4±12.6 100 Group 2 (ZOCOR ^(R )) 187.0±24.6 77.1 Group 3 (sustained release formulation of Example 5) 157.0±18.0 64.8 Group 4 (Normal) 120.3±10.1 - ^* Mean concentration of triglycerides ± standard deviation

As shown in Tables 5 and 6, the blood levels of cholesterol and triglyceride in the first group increased 8-fold and 2-fold, respectively, compared to the fourth group (control) due to the high-cholesterol diet for two weeks. In the second group (ZOCOR(R)) and the third group (sustained release formulation of Example 5), when subjected to two weeks of high cholesterol diet and drugs, their blood levels of total cholesterol and triglycerides were significantly lower than those of the control group blood levels of total cholesterol and triglycerides. In particular, the sustained-release formulation of the present invention showed a higher inhibitory effect on increasing blood levels of total cholesterol and triglycerides than the previous simvastatin rapid-release formulation due to the prolonged action of the sustained-release formulation in the liver .

Although the present invention has been described by the above detailed embodiments, various modifications and changes of the present invention by those skilled in the art should be recognized within the scope of the invention as defined by the appended claims.

Claims (17)

1. extended release preparation that is used for oral administration of HMG-CoA reductase inhibitor, it contains:

Solid dispersion, it comprises HMG-CoA reductase inhibitor, solubilizing agent and stabilizing agent;

Continue to discharge complex carrier; With

Gel hydration accelerator.

2. the extended release preparation of claim 1, wherein based on the HMG-CoA reductase inhibitor of 1 weight portion, solubilizing agent is the 0.05-20 weight portion; Stabilizing agent is the 0.01-0.1 weight portion; Continuing to discharge complex carrier is the 3-30 weight portion; With gel hydration accelerator be the 0.1-5 weight portion.

3. the extended release preparation of claim 1, wherein his spit of fland, simvastatin and its medicinal acceptable salt are cut down in the lactone, velostatin, simvastatin, rivastatin, Fluvastatin, the holder that are selected from mevastatin, lovastatin, pravastatin, pravastatin of HMG-CoA reductase inhibitor.

4. the extended release preparation of claim 3, wherein the HMG-CoA reductase inhibitor is simvastatin or its medicinal acceptable salt.

5. the extended release preparation of claim 1, wherein solubilizing agent is selected from d-alpha-tocopherol cetomacrogol 1000 succinate, Myrj 45, Polyethylene Glycol and polyoxypropylene-polyoxypropylene block copolymers.

6. the extended release preparation of claim 1, wherein stabilizing agent is selected from Yoshinox BHT, butylatedhydroxyanisole, arabo-ascorbic acid and ascorbic acid.

7. the extended release preparation of claim 1, wherein solid dispersion further comprises medicinal acceptable solubilizing carrier.

8. the extended release preparation of claim 1, wherein continuing to discharge complex carrier is the mixture of sodium alginate and xanthan gum.

9. the extended release preparation of claim 8 wherein continues to discharge complex carrier and comprises xanthan gum based on the 0.1-10 weight portion of 1 weight portion sodium alginate.

10. the extended release preparation of claim 8 wherein continues to discharge complex carrier and further comprises locust bean gum.

11. the extended release preparation of claim 10, wherein lasting release complex carrier comprises the locust bean gum based on the 0.1-5 weight portion of 1 weight portion sodium alginate.

12. the extended release preparation of claim 1, wherein gel hydration accelerator is the mixture of propylene glycol alginate and hydroxypropyl emthylcellulose.

13. the extended release preparation of claim 12, wherein gel hydration accelerator comprises the propylene glycol alginate based on the 0.05-20 weight portion of 1 weight portion hydroxypropyl emthylcellulose.

14. the extended release preparation of claim 13, wherein hydroxypropyl emthylcellulose has 4,000-100, the viscosity of 000cps.

15. the extended release preparation of claim 1 further comprises the medicinal additive of accepting that is selected from binding agent, lubricant, sweeting agent and excipient.

16. a method that is used to prepare the extended release preparation of claim 1 may further comprise the steps:

(1) in solvent, mixes HMG-CoA reductase inhibitor, solubilizing agent and stabilizing agent to obtain solid dispersion;

(2) make the lasting complex carrier and gel hydration accelerator and solid dispersion uniform mixing of discharging to form first mixture;

(3) in first mixture, add the medicinal additive of accepting to form second mixture; With

(4) dry mixed and prepare second mixture and become solid preparation.

17. the method for claim 16, wherein solid dispersion is by being selected from following method preparation: spray drying method, solvent evaporated method, wet comminuting method, fusion method and lyophilization.

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